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Mission Statement

As part of the federal government’s National Institutes of Health (NIH), the National Eye Institute’s mission is to “conduct and support research, training, health information dissemination, and other programs with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight, and the special health problems and requirements of the blind.”

Neuron-Glia Interactions in Retinal Disease Section

The mission of our section (NGIRDS) is to explore and understand the fundamental biological mechanisms underlying retinal diseases and translate these findings into proof-of-concept clinical studies to discover new therapies. We have the following starting point: that discovering the interactions between the cellular (neuronal and glia) components of the retina and elucidating how these may be pathological altered are central to the understanding and management of retinal disease. Because many retinal diseases such as diabetic retinopathy, retinal vein occlusions, age-related macular degeneration, involve a key inflammatory component, NGIRDS has focused on the study of the resident immune cell in the retina, the microglial cell, and how it interacts with other retinal cells in the healthy and diseased retina. We have summarized some or our perspectives on how microglia function in the retina in a recent review (Silverman and Wong, Annu Rev Vis Sci., 2018).

About Our Work:

Our unit operates at 3 levels with a central focus on retinal microglia:

Basic scientific study of the retina, addressing the cellular mechanisms in the healthy retina: Basic study of the microglia cell in the retina, involving its morphology, physiology, and cellular interactions with other retinal cell types

Translational study of the retina in disease models: Preclinical study of the involvement of retinal microglia in the aging retina, and in models of retinal disease

Clinical study of retinal diseases and its manifestations: Clinical study of the inflammatory involvement in common retinal diseases, including the targeting inflammation and microglial activation as a therapeutic strategy in proof-of-concept Phase I/II clinical trials.

Our key areas of work are:

Understanding the basic physiology of microglia in the retina:

Given that microglia are the primary resident immune cell type in the retina, we aim to investigate the following questions: What everyday roles do microglia play in the healthy adult retina? What kinds of communications exist between microglia and the surrounding retina neurons and glia? What signals arising from retinal cells help organize the distribution, morphology, and activation states of microglia and maintain their homeostasis? The answers are central to elucidating the basic function of microglia and are relevant to establishing a foundation for the development of therapeutic approaches aimed at microglial modulation as a strategy for retinal diseases.

What constitutive functions do microglia play in the healthy adult retina? We had examined how microglia contribute to normal neuronal function in the uninjured adult retina by depleting microglia in a genetic model (Wang, Zhao et al., J. Neurosci., 2016) over a sustained period of time. We found no significant changes in the: (1) laminar appearance or thickness in the retina, (2) densities of neuronal populations (RGCs, amacrine cells, bipolar cells, horizontal cells, rod or cone photoreceptors, or (3) morphology of retinal neurons and macroglia (astrocytes and Müller cells). However, on functional evaluation, we found that sustained microglial depletion resulted in the progressive deterioration in the electroretinographic (ERG) response, which were correlated with synaptic degeneration that was appreciable on the level of electron microscopy. Our study was the first to show a requirement for microglia in the maintenance of synaptic integrity in the CNS, and reveal the place that microglia have in the healthy function of the retina.

The requirement for microglia in the healthy retina is also evident in the mechanisms that maintain microglial homeostasis under normal conditions. We found that perturbations, such as depleting the retina of microglia, induces a spontaneous recovery of microglial numbers and organization that fully recapitulates the status quo. This response is driven by the proliferation and migration of residual microglia, under the guidance of neuron-to-microglia signals, such as CX3CL1-CX3CR1 signaling (Zhang, Zhao, et al., Science Advances, 2018).

To understand how microglia undergo change in the aging retina and how this contributes to age-related retinal disease:

Our research in Focus Area 1 revealed that microglia in the young healthy adult retina are highly integrated into their environment and continually exchange signals with retinal cells in functionally significant ways. With aging, both microglia and their environment can undergo progressive senescent changes that alter the balance of this relationship. As retinal microglia are long lived cells with tenures extending across much of an animal’s lifespan, we explore in this focus area the following hypotheses:(1) microglia features are not static but instead develop aging phenotypes that are functionally significant, (2) the development of aging phenotypes in microglia are driven by cell-autonomous and environmental factors, and (3) microglial senescent changes help confer on the aged retina an increased vulnerability to disease. In our previous work, we demonstrated that retinal microglia in mouse models do indeed demonstrate senescent changes in terms of their morphology, dynamic process motility, and distribution (Damani et al., Aging Cell, 2011). We discovered that aged microglia display an altered response to injury signals, being slower to respond to acute injury but also slower to revert back to a resting state following injury resolution. These aging phenotypes support the notion that aged microglia decline in their ability to carry out constitutive functions, and respond to injury in a more dysregulated and less reversible way, contributing to greater chronic pro-inflammatory activation states associated with aging (Wong, Front Cell Neurosci. 2013; Ma and Wong, Adv Exp Med Biol., 2016). We discovered through gene profiling studies that retinal microglia demonstrate progressive changes in the expression of genes involved in immune function, angiogenesis, trophic factors, and complement regulation (Ma et al., Neurobiology of Aging, 2013a). We also found that aging microglia accumulate (1) A2E, the primary bisretinoid constitutent of ocular lipofuscin, and (2) 7-ketocholesterol, an oxidized lipid. These factors whose levels increase with aging in the retina, conferred onto microglia a phenotype favoring greater pro-inflammatory and pro-angiogenic influences, and increased complement activation (Ma et al., Neurobiology of Aging, 2013b, Indaram et al., Scientific Reports, 2015).

To understand how microglia are altered in retinal disease, how they may drive disease progression, and how they can be inhibited in preclinical experiments and in clinical trials:

In Focus Area 3, we study how microglia and other innate immune cells in the retina are altered in the context of retinal disease and contribute to disease progression. We are interested in (1) understanding the cellular and molecular mechanisms involved in the pathological interactions between microglia and affected retinal cells, (2) discovering therapeutic agents and new strategies for intervention, and (3) conducting proof-of-concept clinical studies that can demonstrate microglial modulation as a therapeutic strategy. We have previously discovered in a mouse model for retinitis pigmentosa (RP) that microglia can contribute non-cell autonomously to the overall rate of photoreceptor degeneration in RP via phagocytosis and pro-inflammatory mechanisms (Zhao, Zabel et al., EMBO Mol. Med. 2015). We discovered that the following molecular mechanisms are involved: (1) phagocytosis via the vitronectin receptor, (2) production of the inflammatory cytokine IL1β, and (3) CX3CL1-CX3CR1 signaling between retinal neurons and microglia that regulates microglial phagocytosis and activation (Zabel, Zhao et al., Glia, 2016). We also recently discovered that tamoxifen, a drug previously associated with retinal toxicity, paradoxically conferred protection to photoreceptors via its ability to suppress microglia activation (Wang et al., J. Neuroscience, 2017). These studies together outline the contributions that retinal microglia can make to photoreceptor degeneration and highlight some candidate pathways and pharmacological agents that can be exploited for the therapeutic strategy of microglial modulation to ameliorate photoreceptor loss in a variety of retinal diseases.

In addition, we are also interested in further investigating the roles of resident microglia vs. infiltrating monocytes in modulating overall immune responses in the injured retina. Our recent work has uncovered the presence of infiltrating monocytes in different models of retinal injury (Ma et al., Sci. Reports, 2018; Zhao, Zabel., EMBO Mol. Med. 2015), that respond to both neural injury and the need to restore homeostasis to the myeloid cell population in the retina. How these populations and responses contribute in disease and how they should be modulated form part of our future translational goals.